Autoimmunity
Abstract
FOXP3+ Treg cells are critical for immune tolerance. Genetic deletion of the Forkhead domain containing proteins of the FOXP-subfamily member FOXP1 from Tregs results in impaired function associated with reduced CD25 expression and IL-2 signaling, but to date the only other FOXP family member expressed in Tregs, FOXP4, has been minimally studied. To investigate the potential functional interactions among FOXP family members in Treg cells, we specifically deleted Foxp1, Foxp4 or both in FOXP3+ committed Treg cells in mice. Our findings show that mice with combined, but not individual, deficiency in FOXP1 and FOXP4 exhibit lymphoproliferation, inflammation, autoimmunity, and early lethality. The combined absence of FOXP1 and FOXP4 in Tregs results in an activated/effector-like phenotype with compromised suppressive function in peripheral lymphoid organs, an enhanced germinal center response and proinflammatory cytokine production. We further show that FOXP1 and FOXP4 bind to Il2ra promoter regions to regulate CD25 expression in Tregs. Through pairwise comparison among mouse strains with Treg specific deletion of Foxp1, Foxp4 or both, our findings indicate a non-redundant but insufficient role of FOXP4 in Treg cell function.
Authors
Dachuan Dong, Vishal J. Sindhava, Ananthakrishnan Ganesan, Martin S. Naradikian, Tom L. Stephen, Andrew Frisch, Kristen M. Valentine, Elizabeth Buza, Karla R. Wiehagen, Michael P. Cancro, Edward E. Morrisey, Haley Tucker, Katrina K. Hoyer, Purvesh Khatri, Jonathan S. Maltzman
Abstract
Regulatory T cells (Tregs) are essential for peripheral tolerance and depend on TCR and IL-2R signaling for their homeostasis and function. In mice, IL-2-dependent BLIMP-1 contributes to Treg homeostasis. BLIMP-1 is a major transcriptional hub in human Tregs, but its mechanisms of action remain undefined. Here, using CRISPR/Cas9 ablation, we show that BLIMP-1 limits human Treg proliferation, but supports IL-10, CTLA4, several immune checkpoints, including CEACAM1, and Treg functional activity. BLIMP-1 restrains Treg expansion to IL-2 by downregulating CD25 and IL-2R signaling, and by enhancing CEACAM1 expression, which in turn inhibits responsiveness to CD3/CD28 signaling and activation of mTOR. Prolonged IL-2R signaling optimizes BLIMP-1 expression, supporting chromosomal opening of CEACAM1 to increased CEACAM1 expression through STAT5- and BLIMP-1-driven enhancers. Correspondingly, CEACAM1 is highly induced on Tregs from autoimmune patients undergoing low-dose IL-2 therapy, and these Tregs showed reduced proliferation. A humanized mouse model of xenogeneic graft versus host disease demonstrates that BLIMP-1 normally promotes, while CEACAM1 restrains, Treg suppressive activity. Collectively, our findings reveal that BLIMP-1 and CEACAM1 function in an IL-2-dependent feedback loop to restrain Treg proliferation and affect suppressive function. CEACAM1 also acts as a highly selective biomarker of IL-2R signaling in human T cells.
Authors
Ying Ding, Aixin Yu, Milos Vujanac, Sabrina N. Copsel, Alejandro Moro, Luis Nivelo, Molly Dalzell, Nicolas Tchitchek, Michelle Rosenzwajg, Alejandro V. Villarino, Robert B. Levy, David Klatzmann, Thomas R. Malek
Abstract
Spondyloarthritis (SpA) is an inflammatory arthritis of the spine and joints associated with intestinal inflammation, in which it is hypothesized that innate immune exposure to entero-invasive species is followed by self/bacterial peptide presentation. However, the mechanisms underlying loss of tolerance to gut bacteria in genetically at-risk individuals are unclear. Curdlan (β-1,3-glucan, dectin-1 ligand)-treated ZAP-70W163C (SKG) mice develop autoimmune arthritis and ileitis associated with Gram-negative faecal dysbiosis. Using gnotobiotic mice, we show that curdlan-treated SKG mice mono-associated with Parabacteroides goldsteinii or Lactobacillus murinus developed ileitis, arthritis and enthesitis, while BALB/c mice were tolerant. Gnotobiotic SKG ileum upregulated Il23a and ER stress genes and lost goblet cells. Whereas bacterial DNA co-localised with neutrophils and inflammatory macrophages in SKG lamina propria, peri-articular bone marrow, entheses and spleen, in BALB/c bacterial DNA co-localised with resident macrophages in lamina propria and spleen. Human psoriatic-arthritis synovial tissue also contained cell-associated peri-vascular bacterial DNA. Curdlan-treated SKG spleen/bone marrow macrophages transferred severe arthritis and expanded Th17 cells in naïve SKG recipients, while BALB/c or germ free-SKG macrophages transferred mild arthritis and regulated Th17 cells. Thus, bacterial DNA and myeloid cells in the gut and their subsequent traffic regulate or enforce T cell pathogenicity in SpA.
Authors
Benjamin Cai, Rabina Giri, Amy J. Cameron, M. Arifur Rahman, Annabelle Small, Christopher Altmann, Yenkai Lim, Linda M. Rehaume, Mark Morrison, Mihir D. Wechalekar, Jakob Begun, Anne-Sophie Bergot, Ranjeny Thomas
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.185581.
Abstract
Reprogramming autoreactive CD4⁺ effector T (Teff) cells into immunosuppressive regulatory T (Treg) cells represents a promising strategy for treating established autoimmune diseases. However, the stability and function of such reprogrammed Tregs under inflammatory conditions remain unclear. Here, we show that epigenetic activation of core Treg identity genes in Teff cells yields lineage-stable Effector T cell Reprogrammed Tregs (ER-Tregs). A single adoptive transfer of ER-Tregs not only prevents autoimmune neuroinflammation in mice when given before disease onset but also arrests its progression when administered after onset. Compared to Foxp3 overexpressing Teff cells, induced Tregs from naïve precursors, and endogenous Tregs, ER Tregs provide superior protection against autoimmune neuroinflammation. This enhanced efficacy stems from their inherited autoantigen specificity and selectively preserved effector cell transcriptional programs, which together bolster their fitness in inflammatory environments and enhance their suppressive capacity. Our results establish epigenetic reprogramming of autoreactive Teff cells as an effective approach to generate potent, stable Tregs for the treatment of refractory autoimmune conditions.
Authors
Tyler R. Colson, James J. Cameron, Hayley I. Muendlein, Mei-An Nolan, Jamie L. Leiriao, James H. Kim, Alexander N. Poltorak, Xudong Li
Citation Information: JCI Insight. 2025;10(14):e189858. https://doi.org/10.1172/jci.insight.189858.
Abstract
Cellular metabolism plays a key role in T cell biology. Increased glycolysis and mitochondrial respiration have been identified in CD4+ helper T cells from both patients with systemic lupus erythematosus (SLE) and lupus mouse models. Inhibiting this metabolic activity can reduce T cell activation and ameliorate disease symptoms in lupus mice. However, the metabolic differences among circulating follicular helper T (cTfh) cell subsets in patients with SLE versus healthy controls (HCs) have not been thoroughly studied. While the frequencies of cTfh cells and their subsets were similar between patients with SLE and HCs, patients exhibited a higher proportion of activated ICOS+ programmed cell death 1–positive cells, which correlated with disease activity. cTfh17 cells from both patients with SLE and HCs demonstrated heightened glycolytic activity and expression of glycolysis-related genes compared with cTfh1 and cTfh2. Glucose deprivation significantly diminished costimulatory molecule expression and cytokine production, including IL-17A, IL-10, IL-2, and TNF-α. Glycolysis inhibition reduced the B cell activation capacity of cTfh17 cells. This glucose dependence was more pronounced in cTfh17 than cTfh2 from patients with SLE, but it similarly affected both cTfh2 and cTfh17 cells from HCs. These findings highlight distinct metabolic dependencies among cTfh subsets and the critical role of glycolysis in cTfh17-mediated B cell activation in SLE.
Authors
Vera Kim, Takaya Misao, Hong Tian, Meggan Mackay, Cynthia Aranow, Sun Jung Kim
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.188951.
Abstract
Extracellular DNA (ecDNA) released from injured and dying cells powerfully induces injurious inflammation. In this study we define the role of ecDNA in systemic vasculitis affecting the kidney, using human kidney biopsies and murine models of myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (MPO-ANCA GN). Twice daily administration of intravenous DNase I (ivDNase I) in two models of anti-MPO GN reduced glomerular deposition of ecDNA, histological injury, leukocyte infiltration and NETosis. Comprehensive investigation into DNase I modes of action revealed that after exposure to MPO, DNase I reduced lymph node DC numbers and their activation status, resulting in decreased frequency of MPO-specific CD4 effector T cells (IFN-, and IL-17A producing), and reductions in dermal anti-MPO delayed type hypersensitivity responses. To overcome the translational obstacle of the short half-life of DNase I (<5 hours), we tested an adeno-associated viral vector encoding DNase I (vec-DNase I). The method of DNase I delivery was more effective, as in addition to the histological and anti-inflammatory changes described above, a single vector treatment also reduced circulating MPO-ANCA titers and albuminuria. These results indicate ecDNA is a potent driver of anti-MPO GN and that DNase I is a potential therapeutic that can be delivered using gene technology
Authors
Anne Cao Le, Virginie Oudin, Jonathan Dick, Maliha A. Alikhan, Timothy A. Gottschalk, Lu Lu, Kate E. Lawlor, Daniel Koo Yuk Cheong, Mawj Mandwie, Ian E. Alexander, A R. Kitching, Poh-Yi Gan, Grant J. Logan, Kim M. O'Sullivan
Citation Information: JCI Insight. 2025;10(13):e188843. https://doi.org/10.1172/jci.insight.188843.
Abstract
Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, but their use is limited by the development of autoimmunity in healthy tissues as a side effect of treatment. Such immune-related adverse events (IrAE) contribute to hospitalizations, cancer treatment interruption, and even premature death. ICI-induced autoimmune diabetes mellitus (ICI-T1DM) is a life-threatening IrAE that presents with rapid pancreatic β-islet cell destruction leading to hyperglycemia and life-long insulin dependence. While prior reports have focused on CD8+ T cells, the role for CD4+ T cells in ICI-T1DM is less understood. We identify expansion of CD4+ T follicular helper (Tfh) cells expressing IL-21 and IFN-γ as a hallmark of ICI-T1DM. Furthermore, we show that both IL-21 and IFN-γ are critical cytokines for autoimmune attack in ICI-T1DM. Because IL-21 and IFN-γ both signal through JAK/STAT pathways, we reasoned that JAK inhibitors (JAKi) may protect against ICI-T1DM. Indeed, JAKi provide robust in vivo protection against ICI-T1DM in a mouse model that is associated with decreased islet-infiltrating Tfh cells. Moreover, JAKi therapy impaired Tfh cell differentiation in patients with ICI-T1DM. These studies highlight CD4+ Tfh cells as underrecognized but critical mediators of ICI-T1DM that may be targeted with JAKi to prevent this grave IrAE.
Authors
Nicole L. Huang, Jessica G. Ortega, Kyleigh Kimbrell, Joah Lee, Lauren N. Scott, Esther M. Peluso, Sarah J. Wang, Ellie Y. Kao, Kristy Kim, Jarod Olay, Jaden N. Nguyen, Zoe Quandt, Trevor E. Angell, Maureen A. Su, Melissa G. Lechner
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.184240.
Abstract
Multiple sclerosis is characterized by CNS infiltration of auto-reactive immune cells that drive both acute inflammatory demyelination and chronic progressive axonal and neuronal injury. Expanding evidence implicates CD8+ anti-neural T cells in the irreversible neurodegeneration that underlies progression in multiple sclerosis, yet therapies specifically targeting this cell population are limited. CD8+ T cells from patients with MS exhibit increased engagement of the pentose phosphate pathway. Pharmacologic inhibition of the pentose phosphate pathway reduced glycolysis, glucose uptake, NADPH production, ATP production, proliferation, and proinflammatory cytokine secretion in CD8+ T cells activated by ligation of CD3 and CD28. Pentose phosphate pathway inhibition also prevented CD8+ T cell-mediated antigen-specific neuronal injury in vitro and in both an adoptive transfer-based cuprizone model of demyelination and in mice with experimental autoimmune encephalomyelitis. Notably, transcriptional profiling of CNS-infiltrating CD8+ T cells in patients with MS indicated increased pentose phosphate pathway engagement, suggesting that this pathway is involved in CD8+ T cell-mediated injury of axons and neurons in the demyelinated CNS. Inhibiting the pentose phosphate pathway disrupts CD8+ T cell metabolic reprogramming and effector functions, suggesting that such inhibition may serve as a therapeutic strategy to prevent neurodegeneration in patients with progressive MS.
Authors
Ethan M. Grund, Benjamin D.S. Clarkson, Susanna Pucci, Maria S. Westphal, Carolina Muniz Partida, Sara A. Muhammad, Charles L. Howe
Citation Information: JCI Insight. 2025;10(10):e187392. https://doi.org/10.1172/jci.insight.187392.
Abstract
The presence of B cells in tumors is correlated with favorable prognosis and efficient response to immunotherapy. While tumor-reactive antibodies have been detected in several cancer types, identifying antibodies that specifically target tumor-associated antigens remains a challenge. Here, we investigated the antibodies spontaneously elicited during breast and lung cancer that bind the cancer-associated antigen MET. We screened patients with lung (n = 25) and breast (n = 75) cancer and found that 13% had antibodies binding to both the recombinant ectodomain of MET, and the ligand binding part of MET, SEMA. MET binding in the breast cancer cohort was significantly correlated with hormone receptor–positive status. We further conducted immunoglobulin sequencing of peripheral MET-enriched B cells from 6 MET-reactive patients. The MET-enriched B cell repertoire was found to be polyclonal and prone to non-IgG1 subclass. Nine monoclonal antibodies were cloned and analyzed, and these exhibited MET binding, low thermostability, and high polyreactivity. Among these, antibodies 87B156 and 69B287 effectively bound to tumor cells and inhibited MET-expressing breast cancer cell lines. Overall, our data demonstrate that some patients with breast and lung cancer develop polyreactive antibodies that cross-react with MET. These autoantibodies have a potential contribution to immune responses against tumors.
Authors
Michal Navon, Noam Ben-Shalom, Maya Dadiani, Michael Mor, Ron Yefet, Michal Bakalenik-Gavry, Dana Chat, Nora Balint-Lahat, Iris Barshack, Ilan Tsarfaty, Einav Nili Gal-Yam, Natalia T. Freund
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.188724.
Abstract
Dysregulation of T follicular helper (Tfh) and T follicular regulatory (Tfr) cell homeostasis in germinal centers (GCs) can lead to antibody-mediated autoimmunity. While interleukin-1β (IL-1β) modulates the GC response via IL-1R1 and IL-1R2 receptors on follicular T cells in animal models, its role in humans remains unclear. We analyzed Tfh and Tfr phenotypes in human secondary lymphoid organs (tonsils, spleen, and mesenteric lymph nodes) using flow cytometry, single-cell transcriptomics, and in vitro culture, comparing findings with samples from autoimmune patients. We observed organ-specific Tfh/Tfr phenotypes according to activation status and IL-1 receptor expression. An excess of IL-1R1 over IL-1R2 expression promoted a unique activated Tfr subset with Treg and GC-Tfh features. IL-1β signaling via IL-1R1 enhanced follicular T-cell activation and Tfh-to-Tfr differentiation, while IL-1β inhibition upregulated IL-1R1, indicating a tightly regulated process. In autoimmune patients, high IL-1β and circulating Tfr levels correlated with increased autoantibody production, linking inflammation, IL-1β signaling, and Tfr/Tfh balance. Our findings highlight the critical role of IL-1β in follicular T-cell activation and suggest that targeting IL-1β signaling in Tfh and Tfr cells could be a promising strategy for treating antibody-mediated autoimmune diseases.
Authors
Romain Vaineau, Raphaël Jeger-Madiot, Samir Ali-Moussa, Laura Prudhomme, Hippolyte Debarnot, Nicolas Coatnoan, Johanna Dubois, Marie Binvignat, Hélène Vantomme, Bruno Gouritin, Gwladys Fourcade, Paul Engeroff, Aude Belbézier, Romain Luscan, Françoise Denoyelle, Roberta Lorenzon, Claire Ribet, Michelle Rosenzwajg, Bertrand Bellier, David Klatzmann, Nicolas Tchitchek, Stéphanie Graff-Dubois
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